Activation of TGF-β - SMAD2 signaling by IL-6 drives neuroendocrine differentiation of prostate cancer through p38MAPK

Natani, Sirisha; Sruthi, K; Asha, Sakkarai Mohamed; Khilar, Priyanka; Lakshmi, Pampana Sandhya Venkata; Ummanni, Ramesh

doi:10.1016/j.cellsig.2021.110240

Cited by 20 publications

(13 citation statements)

References 50 publications

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“…NEPC cells themselves acquire the characteristics of stem cells, while conducing to resistance acquisition by surrounding tumor cells [ 19 ]. IL-6, a pleiotropic cytokine, activates the TGF- β /SMAD2 axis and its downstream p38MAPK to drive NED of PCa cells under androgen depletion conditions [ 131 ]. IL-6 derived from TAMs also appears competent to upregulate the expression of parathyroid hormone-related peptide (PTHrP) that is an indicator of NED, which forms a positive loop and leads to enhanced NEPC tumorigenesis in vivo [ 132 ].…”

Section: The Roles Of Macrophages In Tumorigenesismentioning

confidence: 99%

The Roles of Tumor-Associated Macrophages in Prostate Cancer

Han

Deng

et al. 2022

Journal of Oncology

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The morbidity of prostate cancer (PCa) is rising year by year, and it has become the primary cause of tumor-related mortality in males. It is widely accepted that macrophages account for 50% of the tumor mass in solid tumors and have emerged as a crucial participator in multiple stages of PCa, with the huge potential for further treatment. Oftentimes, tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) behave like M2-like phenotypes that modulate malignant hallmarks of tumor lesions, ranging from tumorigenesis to metastasis. Several clinical studies indicated that mean TAM density was higher in human PCa cores versus benign prostatic hyperplasia (BPH), and increased biopsy TAM density potentially predicts worse clinicopathological characteristics as well. Therefore, TAM represents a promising target for therapeutic intervention either alone or in combination with other strategies to halt the “vicious cycle,” thus improving oncological outcomes. Herein, we mainly focus on the fundamental aspects of TAMs in prostate adenocarcinoma, while reviewing the mechanisms responsible for macrophage recruitment and polarization, which has clinical translational implications for the exploitation of potentially effective therapies against TAMs.

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Section: The Roles Of Macrophages In Tumorigenesismentioning

confidence: 99%

The Roles of Tumor-Associated Macrophages in Prostate Cancer

Han

Deng

et al. 2022

Journal of Oncology

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“…Other classical tumorigenic pathways, such as Wnt signaling pathway (KEGG:04310, adjusted p-value = 3.48e-4) and TGF-beta signaling pathway (KEGG:04350, adjusted p-value = 3.30e-5) appear also enriched. In this regard, recent studies analyzed the involvement of Wnt signaling in the proliferation of prostate cancer cells (Ma et al 2022; Wei et al 2022), as well as the involvement and TGF-beta signaling (Natani et al 2022; Xi et al 2022).…”

Section: Resultsmentioning

confidence: 99%

The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer

Armaos

Serra

Núñez-Carpintero

et al. 2022

Preprint

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DNA-binding proteins (DBPs) and in particular transcription factors interact with enhancers and their target genes through enhancer-promoter (E-P) interactions. Technological advancements such as chromosome conformation capture allow to identify E-P interactions, but the protein networks involved have not yet been characterized. Most importantly, the role of nuclear protein networks in human diseases has been so far poorly investigated. Prostate cancer (PrCa) heritability is associated with variations in enhancers that affect specific gene expression. Here, we introduce a novel approach, called Promoter-ENhancer-GUided Interaction Networks (PENGUIN), to identify protein-protein interactions (PPI) in E-P interactions and apply it to our PrCa dataset. PENGUIN integrates chromatin interactions between a promoter and its enhancers defined by high-coverage H3K27ac-HiChIP data, with a tissue-specific PPI network inferred from DNA-binding motifs and refined with gene expression. Among a total of 4,314 E-P networks, PENGUIN performed unsupervised clustering. We functionally validated this clustering procedure by searching for enrichments of specific biological features. We first validated PENGUIN structural classification of E-P networks by showing a clear differential enrichment of the architectural protein CTCF. Next, and directly related to our PrCa case study, we observed that one of our 8 main clusters, containing 273 promoters, is particularly enriched for PrCA associated single nucleotide polymorphisms (SNPs) and oncogenes. Our approach proposes a mechanistic explanation for 208 PrCa SNPs falling either inside the binding sites of DNA-binding proteins (DBPs) or within genes encoding for intermediate proteins bridging E-P contacts. PENGUIN not only confirmed the relevance of key regulators in PrCa, but also identified new candidates for intervention, opening up new directions to identify molecular targets for disease treatment.

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“…Haley Dicken et al mentioned that the interaction between the TGF-β signaling network and the AR signaling axis induces EMT and enables epithelial-derived PCa tumor cells to acquire the NE phenotype (Dicken et al, 2019). Sirisha Natani et al stated that IL-6 induces massive TGF-β secretion, while TGF-β/ SMAD2 signaling activates p38 MAPK and induces NED (Natani et al, 2022). Thus, TGF-β receptor signaling-targeting therapy could inhibit both EMT and NED (Dicken et al, 2019).…”

Section: Tgf-βmentioning

confidence: 99%

Focus on the tumor microenvironment: A seedbed for neuroendocrine prostate cancer

Zhou

et al. 2022

Front. Cell Dev. Biol.

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The tumor microenvironment (TME) is a microecology consisting of tumor and mesenchymal cells and extracellular matrices. The TME plays important regulatory roles in tumor proliferation, invasion, metastasis, and differentiation. Neuroendocrine differentiation (NED) is a mechanism by which castration resistance develops in advanced prostate cancer (PCa). NED is induced after androgen deprivation therapy and neuroendocrine prostate cancer (NEPC) is established finally. NEPC has poor prognosis and short overall survival and is a major cause of death in patients with PCa. Both the cellular and non-cellular components of the TME regulate and induce NEPC formation through various pathways. Insights into the roles of the TME in NEPC evolution, growth, and progression have increased over the past few years. These novel insights will help refine the NEPC formation model and lay the foundation for the discovery of new NEPC therapies targeting the TME.

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Activation of TGF-β - SMAD2 signaling by IL-6 drives neuroendocrine differentiation of prostate cancer through p38MAPK

Cited by 20 publications

References 50 publications

The Roles of Tumor-Associated Macrophages in Prostate Cancer

The Roles of Tumor-Associated Macrophages in Prostate Cancer

The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer

Focus on the tumor microenvironment: A seedbed for neuroendocrine prostate cancer

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